Overexpression of HO-1 Contributes to Sepsis-Induced Immunosuppression by Modulating the Th1/Th2 Balance and Regulatory T-Cell Function

• Published in: The Journal of infectious diseases Vol. 215; no. 10; pp. 1608 - 1618
• Main Authors: Yoon, Seong-Jin, Kim, So-Jin, Lee, Sun-Mee
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 15.05.2017
• Subjects: Animals; Apoptosis - drug effects; Apoptosis - immunology; Heme Oxygenase-1 - analysis; Heme Oxygenase-1 - antagonists & inhibitors; Heme Oxygenase-1 - immunology; Heme Oxygenase-1 - metabolism; Immunocompromised Host; Mice; Mice, Inbred C57BL; PATHOGENESIS AND HOST RESPONSE; Protoporphyrins - pharmacology; Pseudomonas aeruginosa - immunology; Pseudomonas Infections - immunology; Pseudomonas Infections - physiopathology; Sepsis - immunology; Sepsis - physiopathology; T-Lymphocytes, Helper-Inducer - drug effects; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; heme oxygenase; apoptosis; immunosuppression; regulatory T-cells; Th1/Th2 shift; sepsis
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jix142

Background. Countervailing anti-inflammatory response and immunosuppression can cause death in late sepsis. Depletion and dysfunction of T cells are critical for developing sepsis-induced immunosuppression. Heme oxygenase-1 (HO-1) has a regulatory effect on differentiation and function of T cells and anti-inflammatory properties. We therefore investigated the immunosuppressive role of HO-1 in sepsis with a focus on its effects on helper T-cell (Th) differentiation and regulatory T cells (Treg). Methods. Sepsis was induced by cecal ligation and puncture (CLP). Mice were intraperitoneally injected with zinc protoporphyrin (ZnPP; 25 mg/kg), an HO-1 inhibitor, or hemin (20 mg/kg), an HO-1 inducer, at 24 and 36 hours post-CLP. Splenocytes were isolated 48 hours post-CLP. Mice were intranasally infected with Pseudomonas aeruginosa 4 days post-CLP as a secondary pneumonia infection model. Results. ZnPP improved survival and bacterial clearance, whereas hemin had the opposite effect in septic mice. CLP induced lymphocyte apoptosis and a proinflammatory Th1 to anti-inflammatory Th2 shift, which was attenuated by ZnPP. ZnPP attenuated the CLP-induced Treg population and protein expression of inhibitory costimulatory molecules. Furthermore, ZnPP improved survival in the secondary pneumonia infection model. Conclusions. Our findings suggest that HO-1 overexpression contributes to sepsis-induced immunosuppression during late phase sepsis by promoting Th2 polarization and Treg function.